A vascularized patient-derived iPSC liver acinus microphysiology system (vLAMPS) is an innovative precision medicine platform for optimizing clinical trial design for nonalcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease (NAFLD) is a major health crisis with no approved therapeutics and many failures in the clinic. The prevalence of NAFLD is estimated to increase from 25% of the US population in 2015 (~83 million) to over 100 million by 2030, accompanied by an increase in nonalcoholic steatohepatitis (NASH), the progressive form of the disease, that can lead to cirrhosis with liver failure and hepatocellular carcinoma (HCC). Despite its public health importance, there is currently no FDA-approved therapy for any stage of NAFLD. NAFLD/NASH is a complex heterogeneous disorder involving multiple molecular pathways. Development of efficacious pharmacotherapy has been hampered by the limited utility of preclinical drug testing models. Simple cell culture and animal models do not recapitulate the spectrum of NASH phenotypes in humans. Highlighting these species differences, knock-in murine models with the high-risk NASH-associated genetic polymorphism, PNPLA3 I148M, develop hepatic steatosis but do not recapitulate the progressive disease seen in humans. Additionally, heterogeneity in risk of progression of NASH, individual genetic variations modulating risk of fibrosis progression, and presence of NAFLD-associated metabolic comorbidities such as Type 2 diabetes mellitus (T2DM), adds additional complexity. We will implement the vLAMPS to initially characterize both a ?normal? and a NAFLD/NASH vLAMPS generated from primary human liver cells (hepatocytes, liver sinusoidal endothelial cells, stellate and Kupffer cells) and then reproduce the results with induced pluripotent stem cells (iPSCs). We will ultimately generate patient-specific iPSCs of the four cell types from patients in our NAFLD clinic to create patient-specific vLAMPS. We will test two cohorts: 1) patients with the PNPLA3 I 148M variant and 2) patients with the wild-type PNPLA3 to identify the patients who respond to two NAFLD drugs that have or are now going through clinical trials and two control drugs. Importantly, this paradigm circumvents the conundrum of high-risk patients being enrolled in large prolonged studies with a high likelihood of failure being simultaneously disqualified from other potentially beneficial studies/treatments. This approach will prove transformational for clinical trial design by enriching for subjects most likely to benefit from a therapy, and in the future, after more than one currently investigational drugs are approved, for precision medicine to identify the most efficacious therapy for high-risk subgroups.